Carbohydrates play an important role in many fundamental biological processes, as well as in the diagnosis and treatment of human disease. Efficient chemical methods for accessing oligosaccharides and glycoconjugates are crucial for continued progress in the field of glycobiology. Unlike amino acids and nucleotides, which form linear polymers, monosaccharides polymerize into a variety of different stereo- and regioisomeric structures. Control over the stereo- and regioselectivity of chemical glycosidation reactions is, therefore, paramount. However, the selective functionalization of one hydroxyl group in the presence of numerous others poses a significant chemical challenge, and most oligosaccharide syntheses must rely upon elaborate and lengthy protecting group strategies to promote reaction at only the desired site. The research described in this proposal focuses on the development of small-molecule catalysts capable of controlling both the stereochemistry and the regiochemistry of glycosidation reactions. The research approach involves the rational design of hydrogen-bond donor catalysts guided, in part, by protein-carbohydrate interactions found in nature. State-of-the-art synthetic, mechanistic and theoretical tools will facilitate the systematic evaluation and optimization of these catalysts towards the goal of controlling the relative reactivity of different carbohydrate hydroxyl groups. The successful development of this proposed research is anticipated to transform oligosaccharide synthesis, dramatically reducing the time and resources necessary to chemically synthesize complex carbohydrates. Further, fundamental mechanistic findings revealed en route to this goal are anticipated to contribute significantly to our understanding of carbohydrate molecular recognition and to lay the groundwork for catalytic approaches to more diverse site-selective functionalization reactions.